The Host Genetics of Age-Dependent Susceptibility

年龄依赖性易感性的宿主遗传学

基本信息

批准号：
10007171
负责人：
VINEET D MENACHERY
金额：
$ 24.59万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10007171
关键词：
Age Aging Animals Automobile Driving Breathing Candidate Disease Gene Case Fatality Rates Cause of Death Chromosome Mapping Communicable Diseases Coronavirus Infections Data Disease Disease Outbreaks Disease Outcome Elderly Family Foundations Functional disorder Future Genes Genetic Genetic Structures Genetic Variation Goals Health Immune response Immunity Inbred Strains Mice Infection Influenza A virus Link Maps Mediating Mus Outcome Pathogenesis Patients Phenotype Play Population Population Heterogeneity Predisposition Process Quantitative Trait Loci Resistance Respiratory Tract Infections Role SARS coronavirus Severe Acute Respiratory Syndrome Time Treatment outcome Tumor-infiltrating immune cells Variant Viral Load result Virus Virus Diseases age related aged chikungunya genetic element genetic resource genomic locus immune function improved insight mortality mouse genetics mouse model novel older patient phenotypic data population based screening senescence validation studies

项目摘要

Abstract Both aging and host genetics play a critical role in susceptibility to viral infection. In our proposal, we use the Collaborative Cross (CC), a novel mouse genetic resource, to explore how host genetics impacts age dependent susceptibility to infection. Infection with Severe Acute Respiratory Syndrome coronavirus (SARS- CoV), the first outbreak virus of the 21st century, caused a range of respiratory infection with more serve disease observed in patients over the age of 50. Importantly, aging susceptibility is conserved in mouse models of SARS-CoV infection and increased disease is not due to higher viral load in older animals. The results indicate host responses drive differential disease in the aged. However, age-dependent susceptibility is not completely conserved across the genetically diverse CC populations. Screening eleven CC lines with SARS-CoV infection at 18 months old, we identified seven lines with more disease as they aged, three lines equivalent to their younger controls, and one line more resistant as it aged. Together, our preliminary results indicate that certain genetic elements contribute to age-dependent susceptibly to SARS-CoV infection. Building from this screen, we will generate an F2 cross using a CC line with age-dependent susceptibility and a CC line without; we will then challenge both young and aged F2 mice to further characterize genetic loci that contribute to SARS-CoV disease and to identify QTL specifically associated with aging and age-dependent disease. We anticipate that these novel genetic loci will provide a foundation for understanding the role of genetic diversity in SARS-CoV disease and aging processes. We expect the results to also to inform future treatment approaches for elderly patients.

抽象的衰老和宿主遗传学在病毒感染的易感性中都起着关键作用。在我们的建议中，我们使用合作十字架（CC）是一种新型的鼠标遗传资源，用于探索宿主遗传学如何影响年龄依赖感染的敏感性。严重急性呼吸道综合征冠状病毒感染（SARS- CoV）是21世纪的第一次爆发病毒，引起了一系列呼吸道感染在50岁以上的患者中观察到的疾病。 SARS-COV感染和疾病增加的模型并不是由于老年动物的病毒负荷较高。这结果表明，宿主反应驱动了年龄的差异疾病。但是，与年龄有关的敏感性是在遗传多样的CC种群中并非完全保存。筛选11条CC线 SARS-COV感染在18个月大时，我们确定了七种疾病，随着年龄的增长，三行相当于他们的年轻控制，一线线更年龄。在一起，我们的初步结果表明某些遗传元素对SARS-COV感染的年龄依赖性有助于年龄依赖性。建筑在此屏幕上，我们将使用具有年龄依赖性易感性和CC线的CC线生成F2交叉没有;然后，我们将挑战Young和老年F2小鼠，以进一步表征有助于的遗传基因座为了SARS-COV疾病，并确定与衰老和年龄依赖性疾病特别相关的QTL。我们预计这些新颖的遗传基因座将为理解遗传多样性的作用提供基础在SARS-COV疾病和衰老过程中。我们希望结果也能为将来的治疗提供信息老年患者的方法。